Automated container capping/decapping mechanism

ABSTRACT

A sample processing station includes two or more container holders on a platform that is rotatable about a central axis of rotation. Each holder is configured to rotate about a secondary axis of rotation. The station includes a capping/decapping mechanism to cap or decap a container held in one of the container holders and an elevator with a chuck guide that contact the container holder as the chuck is lowered by the elevator to position the chuck with respect to the cap of the container held in the holder and to hold jaws of the container holder in a closed position. In embodiment, the chuck guide includes a yoke with opposed arms and spindles located near distal ends of the arms that engage beveled shoulders of the container holder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation application claiming the benefit under 35 U.S.C.§ 120 of the filing date of non-provisional patent application Ser. No.16/127,539 filed, Sep. 11, 2018, which is a continuation applicationclaiming the benefit under 35 U.S.C. § 120 of the filing date ofnon-provisional patent application Ser. No. 15/954,943 filed Feb. 26,2016, now U.S. Pat. No. 10,132,321, which is a divisional applicationclaiming the benefit under 35 U.S.C. §§ 120, 121 of the filing date ofnon-provisional patent application Ser. No. 13/608,876 filed Sep. 20,2012, now U.S. Pat. No. 9,335,336, which claims the benefit under 35U.S.C. § 119(e) of the filing date of U.S. patent application Ser. No.61/532,765, filed Sep. 9, 2011, the respective disclosures of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to automated sample handlinginstrumentation, systems, processes, and methods.

BACKGROUND OF THE INVENTION

Clinical laboratory work often involves a number of repetitive tasksthat are required to be performed quickly and with high precision. Giventhe desire to provide more rapid and accurate laboratory results, therehas been a recent movement to automate laboratory procedures and assays.Though taking repetitive tasks out of the hands of laboratorytechnicians and having them performed by a machine may provide ergonomicand throughput benefits, the task of automating intricate biologicalprocedures has been fraught with difficulties. One source of thesedifficulties is the fact that biological materials are often complicatedmaterials to work with. Contamination, accuracy, and completeness of anassay or sample processing procedure are ever present concerns when theinstrument is doing the work of a skilled laboratory technician.Nevertheless, automated instruments hold the potential to reduce humanerror and offer a more consistent and repeatable series of samplemanipulations and assays.

Accordingly there exists a need in the art to minimize laboratorytechnician handling time of biological specimens prior to assay, whileensuring that sample processing is completed accurately without the riskof contamination. The present invention addresses these and other needs.

None of the references described or referred to herein are admitted tobe prior art to the claimed invention.

SUMMARY OF THE INVENTION

The present disclosure provides a processing station for automaticallyprocessing a biological sample, comprising: (a) a rotatable platformcapable of mixing a biological sample, wherein the platform rotatesaround a central axis; (b) two or more container holders arranged on theX-Y plane in spatially distinct locations on the rotatable platform,wherein the container holders are adapted to hold different containers(wherein each of the different containers has a different size and/orshape) such that two or more different container holders are present;(c) a capping/decapping mechanism that is capable of capping/decappingthe two or more different containers, wherein each of the two or moredifferent containers have a different shape and/or a different shapedcap; (d) a data scanning mechanism capable of acquiring informationabout a container or its contents, wherein the data scanning mechanismis arranged such that the container can be scanned while positioned inone of the two or more container holders; and (e) a mucoid detectionmechanism.

In one embodiment the processing station further comprises a drip trayarranged to be movably positioned under the one or morecapping/decapping mechanisms. The drip tray is most frequentlytranslatable in the X-Y plane. This translation often comprises rotationabout a tertiary axis that is different than the central axis of therotatable platform. Frequently, the drip tray extends outwardly from thetertiary axis and often the extension is effected by way of an arm,post, plate, panel, or blade extending outwardly from the tertiary axis,in other embodiments the drip tray is translatable in the X-, Y-, and/orZ-planes.

The mucoid detection of the processing station often comprises machinevision, reverse capacitive liquid level detection, or a combinationthereof.

The processing station is also often positioned in a sample processinginstrument comprising a sample input rack, a sample output rack, andincubator, a pipette tip tray, a reagent container, a waste bin forcontaining used consumables such as pipette tips and/or liquid waste.

The processing station frequently comprises an instrument inventorymanagement system. Often the instrument inventor management systemmonitors the Inventory of sample containers and reaction vessels in theinput racks, the incubator(s), and/or the output racks. The instrumentinventory management system also often further monitors the number ofpipette tips positioned in the tip trays and/or the level of waste inthe solid waste bin. The instrument inventory management system isfrequently an automated real-time instrument inventory managementsystem. The instrument inventory management system also frequentlycomprises (1) a camera and an associated image processor, and/or (2) aproximity sensor and a barcode reader. The camera is often staticallymounted in optical communication with at least one instrumentconsumable, but is frequently mounted on the robot arm such that it canbe movably positioned throughout the instrument.

Two or more container holders (e.g., 3 container holders, or more) arefrequently positioned on the periphery of the rotatable platform. Eachcontainer holder is rotatable around an individual secondary axis ofrotation that is different than the secondary axis of each othercontainer holder. In addition, vortexing of sample containers orreaction vessels frequency comprises orbital mixing. The orbital mixingcomprises rotation of the rotatable platform circularly around thecentral axis together with rotation of the two or more container holderscircularly around their secondary axes in a direction opposite of therotation of the rotatable platform.

In one embodiment the processing station comprises a power linecommunication system.

The different shaped containers often comprise containers havingdiffering widths, heights, diameters, and/or a combination thereof.

In one set of embodiments the data scanning mechanism comprises abarcode scanner. The barcode scanner is often utilized to, in additionto barcode scanning, determine the centerline and/or position of abarcode on a sample container or reaction vessel.

A process of automated mucoid strand detection and elimination from asample aspiration device is also provided herein, comprising: (a)placing the sample aspiration device in a vessel containing a biologicalsample, wherein the vessel has closed bottom portion and an open topportion; (b) aspirating at least a portion of the sample; (c)withdrawing the sample aspiration device from the sample; (d) while thesample aspiration device is withdrawn from the sample, imaging at leasta portion of the sample aspiration device and processing the imagingresults to detect whether a mucoid strand is present on the sampleaspiration device, wherein if a mucoid strand is detected, the sample isdispensed into the vessel and steps (a)-(d) are repeated until a mucoidstrand is not detected. Often, if a mucoid strand is detected in step(d), the repeated step (b) is performed in a different portion of thecontainer versus the initial or previous step (b). Also often step (c)comprises separating the sample aspiration device from the fluidremaining in the vessel.

In frequent embodiments the sample aspiration device is imaged withmachine vision and the imaging processing occurs automatically withoutmanual user input. Often imaging comprises imaging of at least the tipof the sample aspiration device.

The sample aspiration device often comprises a pipette tip positionedoperably on a pipettor. Frequently, the pipettor is capable ofperforming capacitive liquid level detection and/or reverse capacitiveliquid level detection.

In the most frequent embodiments the vessel is vortexed prior to step(a), a mucoid strand is detected, the sample is vortexed prior torepeating any process steps after dispense of the sample into thevessel.

In frequent embodiments steps (b) and (c) occur with the sampleaspiration device positioned directly over the open top portion of thevessel.

A system for automated real-time inventory control of consumables withina biological sample handling or assay instrument is also providedherein, comprising: (a) one or more consumable types, each comprisingmore than one unit of the consumable; (b) an image collection device inoptical communication with the one or more consumable types; and (c) animage processor, wherein the image collection device captures an imageof the one or more consumable types and the image is automaticallyprocessed to determine the unit number, position, and/or presence orabsence of the one or more consumable types. In a frequent embodimentthe one or more consumable types are backlit from a position opposed tothe location of the image collection device, such that the imagecollection device is in optical communication with the resultingbacklighting illumination.

In one embodiment the consumable type is a pipette tip, a samplecontainer, a reaction vessel, an input rack, an output rack, or areagent.

In a frequent embodiment the image collection device is staticallymounted in optical communication with the one or more consumable types.Also frequently the image collection device is movably mounted inoptical communication with the one or more consumable types. In suchembodiments the image collection device is often mounted on a robot arm.

In occasional embodiments the image processor is comprised within theimage capture device. In other embodiments, image processing occurs in adevice external to the image capture device, for example, a computer orcomputing mechanism.

In one embodiment the system comprises two or more image capture devicesand image processors. Each of these two or more image capture devices isfrequently in optical communication with at least one consumable type.Often each of the two or more image capture devices is in opticalcommunication with two or more consumable types, in frequent embodimentsthe image capture device is positioned in optical communication with awaste bin wherein the image collection device captures an image of thewaste bin and the image is automatically processed to determine thepresence and/or remaining capacity of the waste bin. Also often theimage capture device captures an image of the one or more consumabletypes and the waste bin in a single image.

In certain embodiment the system further comprises an operatornotification protocol, wherein the operator is notified in real-timeabout the inventory of the one or more consumable types detected duringimaging and image processing.

The system also frequently comprises a power line communication system.

A high throughput, random access automated instrument for processingbiological samples is also provided herein, comprising: (a) a sampleprocessing station; (b) a system for automated real-time inventorycontrol of consumables; (c) a sample input bay configured to hold one ormore sample input racks; (d) a sample output bay configured to hold oneor more sample output racks; (e) a power line communication system; (f)a waste bin; (g) a consumable inventory bay; (h) a robot arm having apipettor operably positioned thereon; (i) a pick-and-place mechanism formoving a container within the instrument; and (j) a user interface.

In a frequent embodiment the instrument comprises an automated systemfor identifying and processing a failed sample processing such that thefailed sample is identifiable to a user of the instrument and/or adownstream automated molecular instrument.

In another frequent embodiment the automated system for identifying andprocessing a failed sample processes the failed sample in a manner thatdoes not affect the overall throughput speed of the instrument.

In one frequent embodiment the instrument further comprises a printermodule for use in printing a barcode on a reaction receptacle or asample container. The printer module is often in data communication witha barcode reader such that a barcode read by the barcode reader can bereproduced by the printer module.

An automated instrument for processing or analysis of a sample is alsoprovided herein comprising: (a) a barcode reader; and (b) a printermodule in data communication with the barcode reader, wherein theprocessing or analysis of the sample comprises automated transfer of atleast a portion of the sample from a first receptacle to a secondreceptacle, and wherein the barcode reader scans a barcode present onthe first receptacle, information associated with the barcode istransferred between the barcode reader and the printer module, and theprinter module prints a barcode on the second receptacle. The firstreceptacle frequently comprises a sample container and the secondreceptacle comprised a reaction vessel. Moreover, the barcode printed onthe second receptacle is often the same barcode present on the firstreceptacle.

In another frequent embodiment the barcode printed on the secondreceptacle is a different barcode versus the barcode present on thefirst receptacle. Often the information associated with the barcodeprinted on the second receptacle comprises the information associatedwith the barcode present on the first receptacle and further comprisesadditional information.

Methods of using the disclosed instruments, mucoid detection processes,and systems to process and/or analyse samples are also frequentembodiments of the present disclosure.

These and other features, aspects, and advantages of the presentinvention will become apparent to those skilled in the art afterconsidering the following detailed description, appended claims andaccompanying drawings.

DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a depiction of one embodiment of a sample processinginstrument of the present disclosure.

FIG. 2 provides a perspective view of one embodiment of the sampleprocessing station of the sample processing instrument of the presentdisclosure.

FIG. 3 provides another perspective view of one embodiment of the sampleprocessing station of the sample processing instrument of the presentdisclosure.

FIG. 4 provides a top view of an exemplary sample processing station,showing exemplary rotational directions of the carousel, samplecontainers and reaction vessel.

FIG. 5 provides a perspective view of an exemplary capping and decappingmechanism.

FIG. 6 provides another perspective view of an exemplary capping anddecapping mechanism.

FIG. 7 provides a perspective view of an exemplary output rack.

FIG. 8 provides another perspective view of an exemplary output rackincluding a cover.

FIG. 9 provides a depiction of another embodiment of a sample handlinginstrument of the present disclosure.

FIG. 10 provides a perspective view of an exemplary sample processingstation, including a pick-and-place mechanism grasping a samplecontainer positioned in the service position.

FIGS. 11-1-11-2 provide one exemplary process flow for LBC specimenprocessing.

FIG. 12 provides a top view of one embodiment of a consumable inventorymanagement system component.

FIG. 13 provides a chart depicting one embodiment of an exemplaryelectronic controller architecture of the present disclosure.

FIG. 14 provides a depiction of one embodiment of a sample handlinginstrument of the present disclosure.

FIG. 15 a depiction of another embodiment of a sample handlinginstrument of the present disclosure.

FIG. 16 a depiction of another embodiment of a sample handlinginstrument of the present disclosure.

FIG. 17 is a depiction of a top view of the sample handling instrumentof FIG. 16 .

FIG. 18 is a depiction of one embodiment of the printer module.

FIG. 19 is a depiction of one exemplary placement of the printer modulein the sample handling instrument adjacent to an output rack.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Unless defined otherwise, all terms of art, notations and otherscientific terms or terminology used herein have the same meaning as iscommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. Many of the techniques and procedures described orreferenced herein are well understood and commonly employed usingconventional methodology by those skilled in the art. As appropriate,procedures involving the use of commercially available kits and reagentsare generally carried out in accordance with manufacturer definedprotocols and/or parameters unless otherwise noted. All patents,applications, published applications and other publications referred toherein are incorporated by reference with regard to each issue for whichthey are cited, and related issues. If a definition set forth in thissection is contrary to or otherwise inconsistent with a definition setforth in the patents, applications, published applications, and otherpublications that are herein incorporated by reference, the definitionset forth in this section prevails over the definition that isincorporated herein by reference.

As used herein, “a” or “an” means “at least one” or “one or more.”

As used herein, a “sample” or “biological sample” refers to a biologicalspecimen such as any tissue or polynucleotide-containing materialobtained from a human. Biological samples in accordance with theinvention include peripheral blood, plasma, serum, bone marrow, urine,bile, mucus, cerebrospinal fluid, stool, exosomes, biopsy tissueincluding lymph nodes, respiratory tissue or exudates, gastrointestinaltissue, cervical swab samples, semen or other body or cellular fluids,tissues, secretions, or materials. Often biological samples are dilutedor contained within a vessel containing diluents, transport media,preservative solution, or other fluids. As such, a biological sample ofthe present invention Is intended to encompass a biological samplecontained within a diluent, transport media, and/or preservative orother fluid intended to hold a biological sample.

As used herein, “reaction vessel” refers to any container, tube, testtube, vial, or other vessel configured to hold fluid and can be utilizedin a molecular, microbiologic, immunologic, or other diagnosticbiological assay. One preferred aspect of reaction vessels of thepresent invention is the ability to withstand a heated (e.g., between35° C.-90° C.) incubation without deforming or leaching chemicals intothe sample contained therein. One exemplary reaction vessel is theAPTIMA® tube (Gen-Probe Incorporated, San Diego, Calif.).

As used herein, “assay instrument,” “automated assay instrument,” and“molecular assay instrument” refer to a biological sample analyzercapable of evaluating a biological sample and rendering a result.Overall, any instrument capable of performing a hybridization assay,amplification assay, sequencing assay, or immunoassay is included inthis definition. A couple of exemplary assay instruments include TIGRIS®and PANTHER® instruments (Gen-Probe Incorporated, San Diego, Calif.).

As used herein, “machine vision” refers to a branch of engineering thatuses computer vision in the analysis of images to extract data forcontrolling a process or activity. See, e.g., A. Hornberg, HANDBOOK OFMACHINE VISION (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2006); C.Steger et al., MACHINE VISION ALGORITHMS AND APPLICATIONS (Wiley-VCHVerlag GmbH & Co. KGaA, Weinheim 2008). A machine vision process istargeted at recognizing the actual objects in an image and assigningproperties to those objects—understanding what they mean.

As used herein, “orbital mixing” refers to a motion that induces astirring effect in a liquid-filled reservoir without requiring a mixingutensil such as a spoon, magnetic particle, or similar, in an exemplaryembodiment of orbital mixing the reservoir is subjected to extraneousforces, such as centripetal force and/or centrifugal force, which inducea stirring effect in the liquid contained therein. In the present sampleprocessing instrument orbital mixing of sample containers and reactionvessels occurs in the sample processing station where, for example, oneor more sample container(s) and/or a reaction vessel(s) are positionedon the periphery of the rotatable platform. Orbital mixing is achievedwhereby the rotatable platform rotates in one direction around a centralaxis and the sample container(s) and/or a reaction vessel(s) rotateconcurrently in an opposite direction than the rotatable platform, eachabout an individual axis that is different than the central axis of therotatable platform as well as the axis of each other sample container orreaction vessel.

As used herein, “robot arm” refers to an electromechanical device thattranslates a payload (e.g., a pipettor, a pick-and-place claw, a camera,a sensor, a capper/decapper, etc.) in the X, Y, and/or Z directions. Afrequent embodiment provides a robot arm capable of movement in the X,Y, and Z directions.

As used herein, “mucoid” refers to any viscous material, such as aviscous colloid or a viscous fluid.

As used herein, “power line communication,” “power line communicationsystem,” or “PLC” refers to use of power lines in the instrument totransmit data signals throughout the instrument. See, e.g., POWER LINECOMMUNICATIONS: THEORY AND APPLICATIONS FOR NARROWBAND AND BROADBANDCOMMUNICATIONS OVER POWER LINES (H. C. Ferreira et al. eds., John Wiley& Sons Ltd. 2010). Power line communications systems operate, forexample, by imposing a modulated carrier signal on the wiring system.

Certain biological samples can be run on a molecular assay directlywithout any sample processing. However, biological samples such asliquid based cytology (LBC) samples often require processing prior toassay. Numerous other biological samples often require processing priorto assay, including cell samples, tissue samples, stool samples, mucussamples, semen samples, cerebrospinal fluid samples, blood samples, bonemarrow samples, serum samples, urine samples, bile samples, respiratorysamples, sputum samples, and exosome samples, among others. Often, it isthe particular assay to be run that requires particular sampleprocessing while permitting assay of a variety of sample types. Forexample, human papillomavirus (HPV) assays, Chlamydia assays, gonorrheaassays, human metapneumovirus assays, Mycoplasma pneumoniae andChlamydophila pneumonia assays, Bordetella pertussis assays, Clostridiumdifficile assays, human metapneumovirus assays, and Parainfluenza virusassays, prostate cancer assays, benign prostatic hyperplasia assays,among others, may be performed on a variety of sample types, but eachsample type may require particular processing prior to being able to runthe assay. Also frequently, the type of assay to be run may dictatewhether and/or what sample processing is required prior running anassay. For example, nucleic acid assays such as hybridization assays,amplification assays, and sequencing assays often require sampleprocessing prior to conducting the assay. Protein assays such assequencing assays and immunoassays also may require sample processingprior to conducting an assay. Although pre assay processing LBC samplesis one preferred use of the present invention, the present invention isuseful for conducting accurate and rapid sample processing of any of theabove sample types for at least the assay types noted above.

Referring to FIG. 1 , the sample processing station (107) isincorporated in an automated instrument including one or more inputracks (103), one or more output racks (104), a robotic arm (112, 407,403), a sample pipettor (406), one or more incubators (105), and anembedded controller. In such an embodiment, the robotic arm (112, 408)moves sample containers (102) and reaction vessels (101) between theinput racks (103), the sample processing station (107) and the outputracks (104). Each of these components is preferably incorporated withinan instrument housing. The sample pipettor (406) transfers specimensfrom sample containers (102), such as liquid based cytology (LBC)specimen containers to reaction vessels (101) (e.g., APTIMA® sampletubes available from Gen-Probe Incorporated, San Diego, Calif.) whilealso performing liquid level detection and reagent dispensing. Thesample processing station (107) preferably is configured to hold thesample containers (102) and reaction vessels (101), perform barcodereading (FIG. 2, 204 ), barcode positioning, specimen mixing, andcapping/uncapping of the sample container and reaction vessel. One ormore incubators (105) are frequently incorporated into the instrumentand are occasionally, such as in the depicted embodiment, adapted tohold one or more sample output racks (104) and utilized to incubate thesample directly within the reaction vessel. Often LBC samples, such assamples collected in a SUREPATH® (Becton Dickinson, Inc., FranklinLakes, N.J.) specimen collection containers (210), often require reagentaddition and heated incubation prior to further processing such as amolecular assay. Other LBC sample types, such as those collected in aTHINPREP® (Hologic, Inc., Bedford, Mass.) device (211), often may notrequire incubation. When heated incubation is not required as part ofsample processing the one or more incubators in the instrument, ifconfigured to hold an output rack, may act as an output queue withtemperature control turned off. The instrument also frequentlyincorporates an embedded controller that manages and processessystem-wide activities by delegating specific tasks to instrument subcomponents or modules. Exemplary system activities includecapping/decapping collection and reaction vessels, vortexing,pick-and-place of collection and reaction vessels, pipetting, wastereservoir monitoring, monitoring consumable inventory, monitoring samplequeues, maintaining run logs, monitoring process controls, monitoringsystem alarms, etc.

Though the instrument is often self-contained, accessories for useoutside the instrument housing can be utilized for the convenience ofthe operator and sample processing efficiency. Accessories of this typeinclude, for example handheld barcode readers, uninterruptible powersupplies, and communication port (e.g., Ethernet, USB, eSATA, FIREWIRE®,Wi-Fi, BLUETOOTH®, THUNDERBOLT®, RS-232, RS-485, etc.) compatibleinstrumentation useful for, for example, updating system configurationfiles, transfer of systems logs, transfer of sample information, etc.

The instrument may also incorporate a software user interface. In oneembodiment the user interface incorporates an integrated touch screenused for operator input, instrument control, status monitoring, anddisplay of sample tracking information. Data input means such as USBports are frequently incorporated, for example, to facilitate systemconfiguration file updates, downloading sample tracking data/run logsand for connection of an external mouse and keyboard.

The instrument also generally incorporates a hardware user interfacewhere a user can access the sample input area, the sample output area,and the consumable area. For example, in one embodiment the instrumentincludes two or more cabinets or drawers on the front of the instrumentto access these areas. In a preferred embodiment, the instrumentincorporates two doors and two drawers, where one drawer (111) can beconfigured to contain the instrument consumables, such as pipette tiptrays (110), sample processing reagents, and another drawer (109) can beconfigured to contain the waste container (108). Although FIG. 1 depictsonly pipette tip trays (110) in consumable drawer (111), one of skill inthe art would understand that additional or replacement containers canbe included in such a drawer to contain sample processing reagents. Inaddition, although the solid and liquid waste container (108) isdepicted as a single container, one of skill in the art would understandthat the waste container (108) may preferably be partitioned orseparated into two independent waste storage areas, one for solid waste(e.g., used pipette tips) and the other for liquid waste (e.g.,discarded sample). FIG. 9 , for example, depicts such an arrangement,including a waste container drawer (402), a liquid waste container (403)and a solid waste container (404).

Turning back to FIG. 1 shows an embodiment where a cabinet can beconfigured to hold one or more output racks (104), which can slide intothe instrument incubators (105). These output racks (104) act as outputqueues for the system. Also in this embodiment, another cabinet can beconfigured to hold one or more input racks (103) (also referred toherein as sample racks).

Since the instrument is configured to handle a variety of sample types,including samples collected in different shaped collection vessels(e.g., 210, 211—collectively 102), in a particularly preferredembodiment this cabinet is configured to hold multiple types of sampleracks. For example, in one embodiment the cabinet is configured to holdsample racks (103) containing THINPREP® and/or SUREPATH® samplecontainers (211, 210, respectively). In a related embodiment each samplerack (103) is configured to hold a single type of specimen such that iftwo racks are present one rack may contain only THINPREP® specimencontainers (211), whereas the other rack contains only SUREPATH®specimen containers (210). In a separate preferred embodiment, eachsample rack (103) is configured to hold two or more different shapedsample vessels, for example a sample rack may hold both THINPREP® andSUREPATH® sample containers. In this embodiment the sample rack (103) isoften configured to hold SUREPATH® sample containers (210) (includingthe corresponding reaction vessels (101)) on one side, and THINPREP®sample containers (211) (including the corresponding reaction vessels(101)) on the opposite side. In use, the sample rack can hold SUREPATH®sample containers and then if flipped upside down, it can hold THINPREP®sample containers.

Additional features may optionally be included as part of each cabinetor drawer, such as indicator lights that can provide visual feedback tothe user regarding the current state of the racks, consumables, or wastecontainers in the instrument. For example, the indicator lights canindicate to the user whether a particular rack is being processed, andtherefore cannot be accessed. In contrast, the lights can also indicateto the user when it is safe to remove a rack that has been processed tomake room for another sample rack. Similar indicator lights can beincluded for the sample output racks and the consumable drawer. In oneembodiment, when the drawers are open, the indicator lights are visibleto the user for visual assistance during interventions.

An exemplary input rack is configured to hold both a sample containerand a reaction vessel. This sample rack is preferably configured to holdmultiple pairs of sample containers and reaction vessels, such that theyare incorporated in a one-to-one ratio, in an alternating fashion. Inthis embodiment the primary action required by the user, after verifyinginstrument consumable levels, to begin sample processing is to load therack with pairs of sample tubes and reaction vessels and insert the rackinto the instrument for sample processing to occur.

With reference to FIGS. 7 and 8 , an exemplary output rack (104) isdepicted that is configured to hold a plurality of reaction vessels. Theinstrument automatically processes the reaction vessels from the inputrack (103) to the output rack (104), where the user can retrieve theoutput rack to be run in an assay. In a preferred embodiment the outputrack is configured to be operable in an automated instrument capable ofperforming a molecular assay. In such an embodiment the user retrievesthe rack containing processed samples in the reaction vessels and, withor without any additional required activities such as attaching a coverto the rack, places the rack in the automated molecular assay instrumentto perform a desired assay. In a less preferred embodiment, the reactionvessels in the sample output rack are manually transferred to a rackconfigured to be operable in an automated molecular assay instrument.

The output rack (104), for example, itself is adapted to receive andhold a plurality of receptacles, which, in certain embodiments, maycomprise tubular containers, such as test tubes or APTIMA® transporttubes. An exemplary output rack is described in U.S. Patent ApplicationPublication No. 2010-0288063. The gap between each pair of adjacentdivider walls in the output rack (104) defines a sample receptaclepacket (302), or receptacle-receiving area, for receiving an individualreceptacle. In one embodiment, pocket-identifying indicia, such asbarcode (301), is provided on the divider walls (110) adjacent eachpocket (302). The indicia, which may also include an alphanumericidentifier, e.g., “A”, “B”, “C”, etc., uniquely identifies each pocket(302). A machine readable label, such as “empty pocket” barcode (303),may be provided within each pocket (302), on the inner side of thepocket 302 to uniquely identify each pocket (302) and to indicate when areceptacle is not present in the pocket 302.

In certain embodiments the output rack comprises a microtiter tray, suchas a 96 well plate. In such embodiments sample can be introduced to themicrotiter tray or output rack directly from the sample tube. Often,however, when incubation is required an intermediate tube is utilizedfor incubation such that that sample is transferred to the intermediatetube from the sample tube, then transferred again from the intermediatetube to the microtiter tray after incubation.

In one frequent embodiment, specimens are tracked within the instrumentby placing matching barcodes on both the sample container and thereaction vessel. For example, an onboard barcode scanner (204) reads thetube barcodes once each tube is placed in the sample processing station.Such a barcode reader is often able to locate the positioning of thebarcode on the sample container or reaction vessel by, for example,identifying the location of one or more edges of a label positioned onthe container or vessel and deducing the location of the barcode on thelabel between the identified edges, or positioned a certain distancefrom a particular edge. All system process controls, tube barcodes,time/date stamps, user information, and system status are frequentlystored in an onboard tracking system that is queryable via samplecontainer or reaction vessel barcode. Frequently, the user can manuallyenter an identifier associated with the barcode by use of an instrumenttouch screen or through the use of an optional handheld barcode scannerto perform a query. The system software can be adapted to monitor theoverall system status, reagent and supply inventories, processedspecimen records, and maintenance. In another embodiment samples aretracked within the system through the use of radio-frequencyidentification (RFID). In such an embodiment, sample-, assay-, reagent-,system status-, user-, time/date stamp-, and/or instrument-relatedinformation can be written or re-written to an RFID tag and trackedand/or updated through sample processing and beyond.

In one embodiment, the instrument incorporates a robotic arm (112, 408)that is translatable in the X, Y, and Z planes to move sample containersand reaction vessels between modules (e.g., the sample processingstation) in the instrument. In a preferred embodiment, the robotic arm(112, 408) incorporates an air-based pipettor system to dispense samplesand reagents into reaction vessels.

In one embodiment the pipettor system is provided as part of an XYZrobotic system (106), including an integrated air-pipettor (406) and atube gripper (405). Most frequently, the pipettor and tube gripper areincorporated on the same robotic arm (405), but each has anindependently operable Z axis. This system frequently has common XY axesand 2 independent Z axes to service the pipettor and tube gripper. Thissystem also frequently comprises a cartesian system with belt driven X,Y and gear driven Z axes. The motors in this system frequently haverotary encoders, home and limit sensors. In a frequent embodiment, therobotic arm can move to any point on the instrument deck within about 2seconds or less.

One example of a contemplated pipettor head (406) is a fully integratedOEM module (available from Tecan Group Ltd., Männedorf, Switzerland)capable of dispensing volumes from 10-10000 μl with a CV of 0.75%. Insuch an embodiment the pipettor head is mounted a Z axis of the roboticarm. In a preferred embodiment the pipettor is compatible with Tecandisposable tips (e.g., 10 μl, 50 μl, 200 μl, 1000 μml, with or withoutfilter), and is an air-based-pipettor that does not require tubing,valves, or syringes. The pipettor head frequently contains advancedon-board pump diagnostics, self-test, and error reporting. Moreover, apreferred pipettor has configurable liquid level detection withintegrated pressure sensor (pLLD), is compatible with externalcapacitive liquid level detection hardware (cLLD), can provide real timestreaming data from one or more pressure sensor(s) for processmonitoring, and has a DiTi presence sensor and DiTi ejection mechanism.

The tube gripper module (405) is often responsible for pick-and-place ofthe sample containers and reaction vessels within the system. In oneembodiment it is mounted to the secondary Z axis on the robotic arm. Ina related embodiment, the gripper mechanism contains a cam disk thatopens and closes the gripper when rotated CW/CCW. In this embodiment thecam disk is optionally driven by a small high torque DC gear motor orstepper motor. A variety of additional gripper mechanisms are alsocontemplated and known in the art.

In another preferred embodiment, such as that depicted in FIG. 9 , theinstrument includes two or more robotic arms (407, 408), each with adedicated pipettor head (406) or tube gripper (405).

In one embodiment, samples are transferred from sample containers (102)to reaction vessels in a serial fashion. For example, an aliquot of asample is taken from one sample container (102) and transferred to areaction vessel (103). Thereafter another, different sample is takenfrom a different sample container (102) and transferred to another,different reaction vessel (101). An exemplary process for transferringand processing the sample in the sample processing station is describedin detail below.

With regard to samples requiring reagent addition and a heatedincubation as part of sample processing, in one embodiment onboardincubators (105) are capable of heating the output racks as a finalprocessing step before they are removed from the instrument. In thisembodiment, each output rack (104) generally contains a single type ofsample—one that requires heated incubation or one that does not. Theincubator modules (105) in this embodiment serve at least twofunctions—sample incubation and as an output queue for the system. Eachincubator module (105) can be configured to contain 1, 2 or multipleslots, each capable of housing an output rack. In an exemplaryembodiment the incubators use Kapton heater foil for heating and passiveconvection flow for cooling. A variety of other incubator configurationsare similarly contemplated for use in the present invention, regardlessof the configuration of the incubator, such as forced air convection,Peltier device heating, resistive heating, circulating heated gas orliquid, etc. In a particularly frequent embodiment, samples located inthe incubator will remain at the temperature set point+/−2° C. at steadystate. In a preferred embodiment, the incubators are surrounded byinsulating material, such as foam insulation.

When samples are incubated in output racks, they are generally incubatedin batches corresponding to the maximum number of positions on theoutput rack, or less. For example, 15 samples, or less, in a single rackmay be incubated at one time. Of course, in practice, one of skill inthe art would appreciate that the number of samples in an output rackcan be more or less than 15 samples depending on the number of slotsavailable in the rack and the number of samples to be processed.

Another aspect of the instrument is that it permits a level oftuneability to provide automated sample processing according toprotocols established by the manufacturer that established theparticular assay to be run. These protocols are most frequently inaccordance with regulatory guidelines and mandates. In a further aspect,the instrument permits automated sample processing according toprotocols established by the manufacturer of the sample collectioncontainer. For example, LBC specimens can be processed in an automatedfashion on the instrument in accordance with, for example, the THINPREP®or SUREPATH® protocol, in a frequent embodiment the sample racks aretagged (such as by way of an RFID tag, a mechanical flag, a uniquemachine readable identifier, machine vision, barcode readers, or anothermeans) such that the instrument will recognize the type of samplepresent in the sample rack, and will automatically run the sampleprocessing protocol that is specific for that type of sample. Whenmultiple different sample racks are present, each containing samplesrequiring a processing protocol that is different from the protocol forany or each other rack, the instrument automatically processes thesamples according to a rule set that balances throughput with time-tonext-result. For example, sample racks containing samples in THINPREP®containers can be loaded on the instrument for processing together withracks containing samples in SUREPATH® containers. FIGS. 11-1 and 11-2present an exemplary process flow for preparing a combination ofTHINPREP® and SUREPATH® specimens in an instrument of the presentdisclosure.

Particularly preferred embodiments of a sample processing instrument ofthe present invention are depicted in FIGS. 14-17 . In these embodimentsa dedicated incubator (504) is provided for healed incubation ofreaction vessels (101) that require incubation. In practice reactionvessels (101) will be placed in the incubator (504) by the pick andplace mechanism (405, 507) after completion of processing in the sampleprocessing station (107). After incubation is complete the react orvessels (101) will be placed into an output rack (104) by the pick andplace mechanism (405, 507). Depending on the throughput desired thenumber of output racks (104) can vary, for example, between 4 (FIG. 14 )to 8 (FIGS. 15-17 ) output racks. However, one of skill in the art wouldappreciate that the number of output racks (104) utilized and/or spacededicated to output rack (104) use can vary to be less than 4 racks ormore than 8 racks. In these embodiments the output racks (104) can berandomly populated with reaction vessels (101) that have been incubatedand reaction vessels (101) that have not been incubated. The compositionof sample types in the output rack (104) in these embodiments willfrequently be determined by the type and number of samples processed bythe laboratory at any particular time, without requiring sample batchingas utilized in the output rack (104) incubating embodiments of thepresent invention.

In practice the embodiments of FIGS. 14-17 often utilize asteady-temperature incubator (504) such that when a reaction vessel(101) is placed in the incubator (504), incubation begins immediately.In such an embodiment, each reaction vessel holder (505) is heated to aparticular predetermined temperature and maintained at that temperatureregardless of whether a reaction vessel (101) is present or not.Alternatively, the incubator may be provided with cycling capabilitysuch that it will quickly heat to a predetermined temperature upon, orafter, placement of a reaction vessel (101) in a reaction vessel holder(505). In another preferred embodiment the incubator is partitioned suchthat portions of the incubator may be individually heated, while otherportions of the incubator (504) remain unheated. The partitions cancomprise individual reaction vessel holders (505) such that eachreaction vessel holder (505) is individually temperature controlled,alternatively, the partitions can comprise blocks of reaction vesselholders (505) such that 2 or more reaction vessel holders (505), forexample about 5, 10, 15, 20, 25, 30, 35, 40, or more reaction vesselholders (505) are temperature controlled as a single unit. In any event,the system controller monitors the incubation timing of each reactionvessel (101) to ensure optimum sample processing in a time-efficientmanner without operator intervention.

The embodiments depicted in FIGS. 14-17 show 130 reaction vessel holdersin the incubator (504), however the number of reaction vessel holders(305) in the incubator (504) can vary over a large range, for examplemore or less than 130, depending on the throughput desired and theincubation time required. For example, for an exemplary incubation timeof 2 hours and an individual sample processing time of one minute, apreferred embodiment incorporates at least about 120 reaction vesselholders (505). In this example a reaction vessel (101) can be introducedto the incubator (504) every minute over the course of 120 minutes suchthat the first introduced reaction vessel (101) completes itsincubation, and can be removed from the incubator (504) to the outputrack, at about the same time the last of the 120 reaction vessel holders(505) is filled. This always leaves an open spot for a new reactionvessel (101) to be introduced to the incubator (504), while maximizingthroughput, but minimizing the space occupied by the incubator (504). Inpractice, such an embodiment will often include additional reactionvessel holders (505) in the incubator in case the pick and placemechanism is occupied with other duties, there are no spaces availablein the output racks (104), or the system overall is occupied, at thetime the initial incubation is complete. If the incubation time is lessthan 2 hours the number of reaction vessel holders (505) can becorrespondingly decreased to maximize throughout. Correspondingly, ifsample processing time is decreased to less than one minute it is oftenpreferred to provide additional reaction vessel holders (505) in theincubator (504) such that a reaction vessel (101) can be placed in theincubator (504) at any time the initial sample processing in the sampleprocessing station (107) is complete.

FIGS. 14-17 also depict an alternative configuration of the solid wastebin (108) and liquid waste container (502), in addition to theconsumable area containing pipette tip trays (110) and reagent container(503).

Although FIGS. 14 and 15 show a single robot arm (112) comprising boththe pipettor (406) and the pick and place mechanism (405), multiplerobot arms, for example 2 or more, are contemplated for example asdepicted in FIGS. 16 and 17 . As shown in FIGS. 16 and 17 a second robotarm (506) is provided with a pick and place mechanism (507), while thefirst robot arm is provided with the pipettor (406). In a relatedalternative embodiment the first robot arm (112) contains both apipettor (406) and a pick and place mechanism (405) and the second robotarm (506) contains a pick and place mechanism (507). This second robotarm (506) often serves all pick and place duties required by theinstrument. Alternatively, the second robot arm (506) is programmed, byway of the controller to move reaction vessels (101) and samplecontainers (102, 210, 211) between, for example, the input racks (103)and the sample processing station (107), movement of sample containers(102, 210, 211) from the sample processing station (107) to the inputracks (103), movement of reaction vessels (101) from the processingstation (107) to the incubator (504) or output racks (104), and/ormovement of reaction vessels (101) from the incubator (504) to theoutput racks (104). Use of multiple robot arms provides multipleadvantages, for example by maximizing throughput while permittinguninterrupted processing in the sample processing station (107).

Process Controls

Ensuring sample processing accuracy and completion is an importantaspect of any biological sample processing process, whether it is manualor automated. In automated processing, however, it becomes increasinglydifficult to determine whether a particular process was carried out, orif it was carried out accurately, since processing often occurs outsidethe view of the user. Moreover, biological samples such as LBC samplesare often complex materials to work with in an automated fashion due to,among other reasons, the frequent occurrence of mucoids, particulates,the risk of contamination between samples, and the presence of specimencollection utensils such as brooms, brushes, spatulas, etc. Mucoids caninterfere with sample aspiration and dispense accuracy since they mayoccasionally hang off the end of a pipette tip after sample aspiration.The increased viscosity of mucoids can also occasionally provide a falseindication of the true sample volume that has been aspirated. Moreover,a hanging mucoid at the end of a robot operated pipettor tip poses asignificant contamination risk as the pipette winds its way over samplecontainers, reaction vessels, and/or reagents on its way to a waste binor other location. Particulates also interfere with sample aspirationand dispense accuracy since they can clog the opening of a pipette tipand give a false indication of the true volume of an aspirated sample,or prevent aspiration altogether.

The present system therefore advantageously provides a variety ofprocess controls with each sample processing protocol to minimize thechance that an incorrectly processed sample is delivered to the user.For example, at each step in the process, encoders, electro-mechanicalflags, liquid level detection, barcode reading, temperature sensors,machine vision, optical sensors, reverse cLLD, and pressure base volumeverification, as described herein, are used to ensure that specimen andsample tubes, as well as reagents and the specimens themselves, havesuccessfully completed each step in the processing protocol.

If a sample processing protocol fails and the sample cannot berecovered, there are a variety of contemplated options for dealing withsuch a failure. In one embodiment, if a sample processing fails, thereaction vessel is drained by the pipettor and placed in the outputrack. When the sample is later processed on the sample assay instrument,the empty reaction vessel generates a liquid level or dispensingfailure. Since the reaction vessel contains the same patient identifyinginformation as its corresponding sample collection container, e.g.,barcode information, the sample processing failure can be automaticallyreported to the laboratory information system (LIS). Alternatively, if asample processing fails, the reaction vessel is placed in the outputrack, but rotated in a manner that the barcode of the vessel cannot beread. Either the user will observe the lack of barcode, or when thesample is processed on the sample assay instrument, the sample assayinstrument will determine that particular slot of the output rack (104)to be empty since it will be unable to read identifying informationabout the reaction vessel in that slot. This empty indication cues theuser to report a processing failure to the LIS since the user willidentify that a reaction vessel is actually present and that reactionvessel is associated with a particular sample collection container. Athird option for dealing with sample processing failure is returning thereaction vessel to the input rack, which optionally leaves an empty slotin the output rack (104). Similar to option two, the user thenidentifies the reaction vessel (101) in the input rack (103), and/or theuser or assay instrument identifies the lack of reaction vessel (101) inthe output rack and reports the sample processing failure to the LIS. Asanother option, the printer on the sample handling instrument canblack-out a barcode present in the tube of a failed sample to ensurethat the sample cannot be accidentally processed on a down-streaminstrument.

Ensuring sample identification accuracy is another problem encounteredwhen automating a sample handling process. For example, as the sample isprepared it is transferred between the sample collection container (102,210, 211) and the reaction vessel (101). Therefore, it is important toensure that the sample in the reaction vessel (101) is correlated withthe sample in the sample container (102, 210, 211) so that the sample isprocessed according to the proper protocol and that the correlation ofthat sample with the donor patient is maintained. To address theseissues the instrument advantageously tracks the identification of eachsample throughout processing, including following the sample as it ispassed from the sample container (102, 210, 211) to the reaction vessel(101). One exemplary method of tracking this information provided hereinis to utilize matching barcodes on both the sample container (102, 210,211) and the reaction vessel (101). This process maintainssample-to-result positive identification tracking. Utilizing thistracking process provides an advantage over existing sample processinginstruments in that matching the tube barcodes and always passing thereaction vessel (101) directly to the sample assay instrument eliminatesthe need for an LIS interface. Moreover, this process greatly simplifiesthe necessary instrument software and tracking process since thedownstream assay instrument is generally connected to an LIS.

The laboratory workflow required to process LBC samples requires thatdoth the LBC sample container (102, 210, 211) and the reaction vessel(101) have the same barcode containing patient identification. Thisenables sample assay instruments such as instruments capable ofperforming hybridization assays, amplification assays, sequencingassays, and/or immunoassays to communicate with the laboratory's LIS.Some laboratories do not have the capability, or their process flow doesnot allow them to, print duplicate barcodes. The present inventionaddresses these problems in a few alternative ways. For example, if thelaboratory has the capability, it can print a barcode containing patientidentification and apply it to the sample container (102, 210, 211). Thereaction vessel (101), in turn, contains a preprinted, unique serialnumber on the tube provided by, for example, the tube manufacturer. Thesample handling instrument then reads both the sample container (102,210, 211) barcode and the reaction vessel (101) barcode and creates anassociation between the two containers. This association information isthen transferred to the sample assay instrument via a network connection(e.g., LAN, Ethernet, WiFi, BLUETOOTH®, ZIGBEE®, RS232, USB, RF, IR,FIREWIRE®, THUNDERBOLT®, eSATA, or other). When the sample assayinstrument encounters a reaction vessel with patient identification thathas the association, the instrument then queries/reports patient dataagainst the associated sample container (102, 210, 211) barcode, whichis loaded into the LIS.

Alternatively, the same scenario as above may occur, with the exceptionthat the association information is stored in a file on a mobile storagedevice such as a USB drive or similar. The mobile storage device isthen, for example, manually plugged into the assay instrument where theinformation is transferred to the instrument. Alternatively, theassociation information is occasionally stored in an RFID tagpositioned, for example, on the output rack. In such an embodiment theRFID tag transmits the information to tie assay instrument uponplacement in the instrument.

Alternatively, the laboratory prints one barcode containing patientidentification and applies it to the sample container (102, 210, 211).The reaction vessel, in turn, contains no label, a blank label, or adifferent label. The sample handling instrument then reads the samplecontainer (102, 210, 211) barcode, prints the same barcode as containedon the sample container (102, 210, 211) (with optional additionalmetadata in the form of barcode prefixes, suffixes or similar) andapplies it to the reaction vessel (101). In a related preferredembodiment, the sample processing instrument reads the sample container(102, 210, 211) barcode, and creates the same barcode (with optionaladditional metadata in the form of barcode prefixes, suffixes orsimilar) directly on the reaction vessel, e.g., by way of printing,imprint, burning, thermal transfer, or another method. Also frequently adifferent bar code is printed on the reaction vessel containingadditional metadata (e.g., time, volume, type, reagents, errors, etc.)related to the processing of the corresponding sample. The barcodes arecreated in the instrument most frequently through the use of a printermodule (600) (FIGS. 18 & 19 pictured) positioned within the instrument.In practice, a sample container is moved from an input rack to thesample processing station to be processed; meanwhile, the correspondingreaction vessel is transferred from the input rack to the printer module(600). The reaction vessel most frequently has a blank label, or a blankarea on the label, where the barcode is to be printed or applied by theprinter module. In practice, the printer module automatically determinesthe orientation of the tube to identify the position to print thebarcode. Often the orientation determination is performed with referenceto edges of the label or other indicia contained on the label. The meansfor barcode printing includes any known printing method, for exampleinkjet, direct thermal, thermal transfer, impact, laser ablation, laserpigment change, etc. It is frequently preferred to utilize thermaltransfer printing in the printer module (600) to eliminate the need forextra consumables, contamination risks, among other reasons. After thebarcode is printed, or otherwise automatically applied, on the reactionvessel it is transferred to the sample processing station forprocessing.

In another alternative embodiment, the sample container (102, 210, 211)contains duplicate barcodes, or more than one barcode, and the sampleprocessing instrument removes one of these barcodes and applies itdirectly on the reaction vessel. The automated assay instrument can thendirectly query the LIS or report to the LIS against the sample container(102, 210, 211) barcode (i.e., patient ID).

In one embodiment, samples are processed one-at-time in the automatedsample handling instrument. For example, when incubation is notrequired, the next sample does not start its processing until thepreceding sample processing is complete. In such an embodiment, therobotic arm pick-and-place mechanism retrieves the sample container(102, 210, 211) and the reaction vessel (101) from the input rack (103).Both containers are moved to the sample processing station (107) where,for example, the barcodes are read (215) by a barcode reader (204) andverified to be a pair. In a preferred embodiment the processing of thesample container begins in the sample processing station prior toarrival of the reaction vessel. In such an embodiment, the reactionvessel is frequently presented to a printer module (600) (FIGS. 18 & 19) by the pick and place mechanism to print a barcode on the reactionvessel prior to its arrival in the sample processing station. Thebarcode printed, or otherwise applied, on the reaction vessel may beidentical to the corresponding sample container or it may be a differentbar code. Often a different bar code is incorporated that encodesadditional metadata relevant to the processing of that particularsample.

Once processing has been completed, the reaction vessel (101) is movedto the output rack (104) and the sample container (102, 210, 211) ismoved back to the input rack (103). All process controls, system status,and user status are logged and associated with the sample barcodes andsaved to persistent storage. At any time, the sample processing log canbe queried for a specific sample by, for example, barcode, RFID, orexported to a file via, for example, a USB drive or similar.

In most diagnostic instrumentation, inventory control and monitoring ishandled by a set of assumptions, rules and feedback mechanisms which arecomplicated, marginally accurate and time consuming. The automatedsample processing instrument of the present invention implements a newconcept for fast, accurate, real time control and monitoring of onboardinventory via machine vision. In practice, each of the inventoried itemsare visibly available to a set of camera(s) that perform imageprocessing algorithms to determine volume, capacity, or inventory of anyonboard consumables, samples, tubes, and waste materials. For example,in one embodiment, one or more cameras are statically mounted on theinstrument frame to provide continuous real-time feedback. In additionor alternatively, as shown in FIGS. 36 and 37 , one or more cameras(508) are mounted on a robotic arm (112, 506) to provide visual feedbackto multiple areas of the instrument. Though FIGS. 16 and 17 depict asingle camera (508) on robot arm (112), another camera can be positionedon the second robot arm (506). Special illumination techniques areprovided to achieve robust, fast and accurate visual feedback. Forexample, a few specific areas of machine vision inventory control thatare often used on the sample processing instrument are as follows:

1. Pipette Tip & Waste Bin Inventory: A camera is mounted above theinstrument looking onto the deck (e.g., FIG. 17 ). The camera is inoptical communication with, and images the pipette tip trays and wastebin. The camera has, for example, onboard image processing capabilities,or is connected to computer or computing apparatus to conduct imageprocessing, and processes the image and provides a full inventory of alltips within the tip trays and waste bin. In one embodiment, backlightillumination under the tips trays and waste bin is provided to reducethe complexity and increase the reliability and speed of the imageprocessing algorithms (see FIG. 12 ). In one embodiment the tip trayand/or waste bin are made of a translucent material to enhance imaging.

2. LBC Specimen tube inventory: A camera is mounted above the instrumentlooking onto the deck (e.g., FIG. 17 ). The camera is in opticalcommunication with, and images, the sample input bay containing thesample container (102, 210, 211) to be processed. The camera, forexample, has onboard image processing capabilities, processes the image,and provides a full inventory of all reaction vessels (101) and samplecontainers (102, 210, 211) present on the instrument. In a relatedembodiment, the camera is utilized to determine the types of samplecontainers (102, 210, 211) and/or types of samples contained in theinput racks (103), for example by identifying markings on the samplecontainer (102, 210, 211) or sample rack (103), or visualizing a barcodecontained on the sample containers (102, 210, 211) or sample rack (103).

3. Single Camera Inventory Control: Alternatively, one or more cameras(508) is/are mounted to an instrument robotic arm (112, 506). The camera(508) is moved around the instrument deck during routine operation ofthe robotic arm (112, 506) or upon special instruction, providing a fullinventory of ail instrument consumables as in cases (1) and (2) above.

As mentioned above, a common problem with specimens collected frompatients is the presence of mucoids. Pipette tips often get clogged orpull mucoid strands from the sample or specimen tube. While clogs canusually be detected with pressure based feedback, mucoid strands may notbe detectable. If mucoids are not properly removed, contamination mayoccur. While shearing mechanisms may work, they may not guarantee mucoidremoval. Thus, the automated sample processing instrument may include amucoid strand detection mechanism. In a preferred embodiment, the mucoidstrand detection mechanism incorporates a machine vision system tovisually inspect all pipette tips immediately after a specimenaspiration and before the pipette tip has been moved away from thespecimen tube. The vision system frequently comprises a camera (such ascamera (509) in FIG. 2 ) with onboard image processing algorithms thatnotify the instrument controller as to whether or not a mucoid strand ispresent.

As a second layer of detection for a mucoid strand detection mechanism,the pipettor (406) is optionally configured to perform reversecapacitive Liquid Level Detection (cLLD) such as described in U.S. Pat.No. 7,479,391. Reverse cLLD detects a change in capacitance of thepipette tip. When the pipette tip is removed from the specimen liquid,cLLD reports a step change in capacitance. This step change occurs atthe liquid level of the specimen (the liquid level is accuratelydetected before aspiration). If the step change is delayed or there isno step change, a mucoid may be present.

When a mucoid strand is detected by either or both processes, thepipettor fully dispenses the sample back into the sample container (102,210, 211) and re-attempts the aspiration. The pipettor may optionallyalter its position within the sample tube to a new aspiration locationto avoid mucoids. If after multiple retries, mucoid strands are stilldetected, the specimen tube is optionally vortexed and the aspirationprocess is repeated. This process has the advantage of providing asignificant guard against contamination versus conventional shearingmechanisms since no mucoid strands leave the sample container (102, 210,211). Furthermore, this method requires little or no maintenance, soroutine instrument cleaning requirements are reduced.

In a frequent embodiment, the automated sample processing instrumentcontains one or more of the following process controls to ensureaccurate and complete sample processing:

-   -   1. Positive sample identification using a barcode reader to read        tubes in the processing station.    -   2. Consumable inventory control of all consumables, the solid        waste bin, the input racks, the output racks, and incubator        inventory, which can identify the number and type of        preparations remaining (e.g., camera-based).    -   3. Reagents volumes confirmed and tracked by liquid level sense        and/or LLD.    -   4. Liquid in waste bin volume tracking by LLD or counting        dispenses.    -   5. Detection of pipettor tip retention and ejection.    -   6. Confirmation of sample delivery by liquid level sense and/or        Pressure Dispense Volume Verification via RDV.    -   7. Confirmation of reagent delivery by liquid level sense and/or        Pressure Dispenser Volume Verification via RDV.    -   8. Mix verification by sensing mechanical motion using sensors        and/or encoders.    -   9. Thermal monitoring of all temperature sensitive modules.    -   10. Encoder feedback to ensure proper robotic motion.    -   11. Machine vision mucoid detection.    -   12. Sensors to detect different sample types (e.g., input        racks).    -   13. Positive ID verification and barcode printing for reaction        vessels in the instrument.

In another frequent embodiment, the automated sample handling instrumentcontains one or more of the following process controls to minimize therisk of contamination:

-   -   1. Filtered disposable pipette tips.    -   2. Cleanable specimen input racks.    -   3. Cleanable output racks.    -   4. Cleanable consumable rack.    -   5. Disposable waste bins or waste bin covers.    -   6. Cleanable drip tray.    -   7. Specimen mucoid removal track.    -   8. Barriers between the tip racks, sample racks, and processing        station.    -   9. Controlled airflow to keep aerosols moving from clean to less        clean side of instrument.    -   10. Easily cleanable surfaces and tracks.    -   11. Instrument covers to protect from splashing the operator.    -   12. Machine vision and reverse cLLD confirmation of sample        aspiration and mucoid detection.

Since the instrument is capable of concurrently processing multiplesample types, some requiring reagent addition and heated incubation andothers not requiring incubation, it is important, to ensure properthermal management. In this regard, in one embodiment the automatedsample processing instrument often contains one or more of the followingitems:

-   -   1. Four or more incubators servicing four or more output racks;        alternatively a single incubator is provided, servicing all        reaction vessels to be incubated.    -   2. Multiple temperature sensors that provide precision incubator        temperature control and redundancy.    -   3. Controlled airflow.    -   4. Insulated incubators that inhibit heat transfer to other        parts of the instrument containing reaction vessels that are not        to be incubated, sample containers, and reagents.

Throughput

The present invention provides an automated high-throughput, randomaccess sample handling instrument capable of simultaneously processingmultiple different sample types. As indicated, the instrumentautomatically processes samples according to a rule set that balancesthroughput with time-to-next-result, which is particularly relevant whenthe instrument is processing different types of samples that requiredifferent routines and reagents. For example, in one embodiment theinstrument is designed to process up to about 540 samples that do notrequire incubation, or up to about 360 samples that require reagentaddition and heated incubation within a single 8 hour shift. Included inthis time is instrument setup, run preparation, sample handling, cleanup and instrument power down. For purposes of this discussion, a “run”is defined as the processing of up to about 60 LCB specimens from startto finish. One of skill in the art would appreciate that a run couldinvolve processing more or fewer samples, depending on the number ofavailable input and output slots on the machine. For example, a runcould refer to the processing of up to about 96 LCB specimens from startto finish. In one embodiment a run refers to processing a collection ofsamples that occupy a defined portion or all of the available inputslots or that occupy a defined portion or all of the available outputslots.

The sample processing protocol that does not require incubation (i.e.,processing THINPREP® samples) is often the LBC preparation protocolexecuted on the instrument having the fewest steps. In a frequentlypreferred embodiment, this protocol takes about 1 minute of processingtime per specimen and thus can process up to 9 runs (e.g., 540 samples)in an 8 hour shift, in this embodiment the time to first result is about1 minute for a single specimen or approximately 15 minutes to prepare afull output rack having 15 slots.

In another embodiment, the protocol takes about 30 seconds of processingtime per specimen, and thus can process up to 18 runs (e.g., 1080samples) in an 8 hour shift. In this embodiment the time to first resultis approximately 30 seconds for a single specimen or approximately 7.5minutes to prepare a full output rack having 15 slots.

The specimen processing time will often depend on the type of processingrequired and the sample type being prepared. The overall sampleprocessing protocol can vary over a range of time, for exampleprocessing of a single sample may range from 30 seconds to 2.5 hours (ifincubation is required). In a frequently preferred embodiment the sampleprocessing time may range between 30 seconds and 2 minutes. In anotherpreferred embodiment the sample processing time may range between about1 to about 2 minutes. If an incubation is required, often sampleprocessing time will range between about 3 hour to about 2.5 hours.

In one embodiment, the flow of processing of a THINPREP® sample,irrespective of concurrently conducted process controls, is thefollowing:

-   -   a. Pick sample container (211) and reaction vessel (101) from        input rack and place in corresponding container holders (206,        203, respectively) on carousel (209) in processing station        (107). Holder (206) includes opposed jaws (206 a, 206 b) and        tension band (217), and holder (208) includes opposed jaws (208        a, 208 b) and tension band (217). Tension bands (217) limit the        amount by which opposed jaws (206 a, 206 b) or (208 a, 208 b)        can be spread apart.    -   b. Read the sample barcode.    -   c. Orbitally mix sample container (211) by rotating carousel        (209) about its center axis and rotating holders (206, 207)        about shafts (214) (see arrows on FIG. 4 ).    -   d. If necessary, pick corresponding reaction vessel (101) from        input rack and place in printer module (600) (FIGS. 18 & 19 )        for barcode printing.    -   e. Pick corresponding reaction vessel (101) from printer module        (600) (FIGS. 18 & 19 ) and place in reaction vessel holder (208)        on carousel (209) in processing station (107).    -   f. Rotate sample container (211) under an elevator (203) holding        capping/decapping mechanism (201) with a chuck (205) that is        lowered by the elevator (203) to grasp the cap (212) (see also        FIGS. 5 & 6 ). Elevator (203) may include a chuck guide (230)        configured to align the chuck (205) with the sample container        (211) and cap (212) as the chuck (205) is lowered onto the cap        (212). FIG. 4 shows operation of elevator (203) and chuck guide        (230) when reaction vessel (101) is positioned under the        elevator (203) by the carousel (209). In the illustrated        embodiment, chuck guide (230) includes a yoke (220) that is        moved up and down with the chuck (205) and includes opposed arms        (222, 224) that contact opposed sides of the holder (208) to        center the chuck (205) with respect to the holder (208) and thus        with respect to reaction vessel (101). In an embodiment, Yoke        (220) has a curved, “horseshoe” shape. Yoke (220) may include        spindles (226, 228), which may be located near distal ends of        arms (222, 224, respectively). Spindles (226, 228) engage        beveled shoulders (208 c, 208 d) of jaws (208 a, 208 b,        respectively) of holder (208) as the chuck (205) is lowered by        elevator (203) to align chuck (205) with reaction vessel (101)        and to hold jaws (208 a, 208 b) in a closed position. Referring        again to FIGS. 2 and 3 and removal of cap (212) from sample        container (211), spindles (226, 228) engage beveled shoulders        (206 c, 206 d) of jaws (206 a, 206 b, respectively) of holder        (206) as the chuck (205) is lowered by elevator (203) to align        chuck (205) with cap (212) and to hold jaws (206 a, 206 b) in a        closed position.    -   g. Uncap Thinprep container (211).    -   h. Elevator (203) moves cap/chuck (212/205) upward, which        permits the carousel (209) to rotate without hitting the cap,        and the drip tray (202) swings under the chuck/cap (212/205).    -   i. Rotate sample container (211) to service position (i.e., the        positioning depicted for container (211) in FIG. 2 ).    -   j. Aspirate sample from sample container (211).    -   k. Move pipettor (406) over liquid waste container (502).    -   l. Rotate sample container (211) under capping/decapping        mechanism (201) and chuck (205).    -   m. Move drip tray (202) out of way of chuck (205).    -   n. Elevator (203) moves capping/decapping mechanism (201)        holding cap/chuck (212/205) downward onto sample container        (211), and drip tray (202) is withdrawn. Arms (222, 224) of yoke        (220) engage opposite sides of the holder (206) to center the        cap/chuck (212/205) with respect to the sample container (211).        In the illustrated embodiment, spindles (222, 224) of elevator        (203) engage beveled shoulders (205 c, 206 d) of Jaws (206 a,        206 b, respectively) to align cap (212) held by chuck (205) with        sample container (211) and to hold jaws (206 a, 206 b) in a        closed position.    -   o. Sample container (211) is recapped.    -   p. Move elevator (203) up to allow carousel (209) to rotate.    -   q. Reaction vessel (101) is rotated under capping/decapping        mechanism (201).    -   r. Elevator (203) is lowered where chuck (205) grasps and        removes reaction vessel cap (216), and arms (222, 224) of yoke        (220) engage opposite sides of the holder (208) to center the        chuck (205) with respect to the reaction vessel (101) and cap        (216). In the illustrated embodiment, spindles (222, 224) of        elevator (203) engage beveled shoulders (208 c, 208 d) of jaws        (208 a, 208 b, respectively) of holder (208) to align chuck        (205) with cap (216) and to hold jaws (208 a, 208 b) in a closed        position.    -   s. Elevator (203) moves cap/chuck (216/205) upward and the drip        tray (202) swings below the cap/chuck (216/205).    -   t. Move drip tray (202) under cap (216).    -   u. Reaction vessel (101) is rotated to the service position.    -   v. Sample is dispensed into the reaction vessel (101).    -   w. Reaction vessel (101) is rotated under capping/decapping        mechanism (201) and chuck (205).    -   x. Drip tray (202) is withdrawn as the elevator (203) moves        cap/chuck (216/205) downward onto reaction vessel (101) to recap        the reaction vessel (101). Arms (222, 224) of yoke (220) engage        opposite sides of the holder (208) to center the cap/chuck        (216/205) with respect to the reaction vessel (101). In the        illustrated embodiment, spindles (222, 224) of elevator (203)        engage beveled shoulders (208 c, 208 d) of jaws (208 a, 208 b,        respectively) to align cap (216) held by chuck (205) with        reaction vessel (101) and to hold jaws (208 a, 208 b) in a        closed position.    -   y. Reaction vessel (101) is recapped.    -   z. Sample container (211) is moved to input rack (103).    -   aa. Reaction vessel is moved to output rack (104).

In one embodiment, the flow of processing of a SUREPATH® sample,irrespective of concurrently conducted process controls, is thefollowing:

-   -   a. Pick sample container (210) and reaction vessel (101) from        input rack and place in corresponding container holders (207,        208, respectively) on carousel (209) in processing station (107)        hoister. Holder (207) includes opposed jaws (207 a, 207 b) and        tension band (217). Tension band (217) limits the amount by        which opposed jaws (207 a, 207 b) can be spread apart.    -   b. Read the sample barcode.    -   c. Mix sample container (210) (see arrows on FIG. 4 ).    -   d. If necessary, pick corresponding reaction vessel (101) from        input rack and place in printer module (600) (FIGS. 18 & 19 )        for barcode printing.    -   e. Pick corresponding reaction vessel (101) from printer module        (600) (FIGS. 18 & 19 ) and place in reaction vessel holder (208)        on carousel (209) in processing station (107).    -   f. Rotate sample container (210) under elevator (203) holding        capping/decapping mechanism (201) where chuck (205) grasps cap        (213) (see also FIGS. 5 & 6 ), and arms (222, 224) of yoke (220)        engage opposite sides of the holder (207) to center the chuck        (205) with respect to the sample container (210) and cap (213).        In the illustrated embodiment, spindles (222, 224) engage        beveled shoulders (207 c, 207 d) of jaws (207 a, 207 b,        respectively) of holder (207) as the chuck (205) is lowered by        elevator (203) to align chuck (205) with cap (213) and to hold        jaws (207 a, 207 b) in a closed position.    -   g. Uncap sample container (210).    -   h. Elevator (203) moves cap/chuck (213/205) upward, which        permits the carousel (209) to rotate without hitting cap (213),        and the drip tray (202) swings under the cap/chuck (233/205).    -   i. Rotate sample container (210) to service position (i.e., the        positioning depicted for container (211) in FIG. 2 ).    -   j. Pipettor (406) aspirates predetermined amount of sample        processing reagent (e.g., FASTEXPRESS® reagent, available from        Gen-probe incorporated, San Diego, Calif.)    -   k. Using the same pipette tip as step (g), or selecting a new        pipette tip, aspirate sample from sample container (210).    -   l. Move pipettor (406) over liquid waste container (502).    -   m. Rotate sample container (210) under capping/decapping        mechanism (201) and chuck (205).    -   n. Elevator (203) moves capping/decapping mechanism (201)        holding cap/chuck (213/205) downward onto sample container (210)        and drip tray (202) is withdrawn. Arms (222, 224) of yoke (220)        engage opposite sides of the holder (207) to center the        cap/chuck (213/205) with respect to the sample container (210).        In the illustrated embodiment, spindles (222, 224) of elevator        (203) engage beveled shoulders (207 c, 207 d) of jaws (207 a,        207 b, respectively) to align cap (213) held by chuck (205) with        sample container (210) and to hold jaws (207 a, 207 b) in a        closed position.    -   o. Sample container (210) is recapped.    -   p. Move elevator (203) up to allow carousel (209) to rotate.    -   q. Reaction vessel (101) is rotated under capping/decapping        mechanism (201).    -   r. Elevator (203) is lowered where chuck (205) grasps and        removes reaction vessel cap (216), and arms (222, 224) of yoke        (220) engage opposite sides of the holder (208) to center the        chuck (205) with respect to the reaction vessel (101) and cap        (216). In the illustrated embodiment, spindles (222, 224) of        elevator (203) engage beveled shoulders (208 c, 208 d) of jaws        (208 a, 208 b, respectively) of holder (208) to align chuck        (205) with cap (216) and to hold jaws (208 a, 208 b) in a closed        position.    -   s. Elevator (203) moves cap/chuck (215/205) upward and the drip        tray (202) swings below the cap/chuck (216/205).    -   t. Reaction vessel (101) is rotated to the service position.    -   u. Sample is dispensed into the reaction vessel (101).    -   v. Reaction vessel is rotated under capping/decapping mechanism        (201) and chuck (205).    -   w. Drip tray (202) is withdrawn as the elevator (203) moves        cap/chuck (216/205) downward onto reaction vessel (101) to recap        the vessel. Arms (222, 224) of yoke (220) engage opposite sides        of the holder (208) to center the cap/chuck (216/205) with        respect to the reaction vessel (101). In the illustrated        embodiment, spindles (222, 224) of elevator (203) engage beveled        shoulders (208 c, 208 d) of jaws (208 a, 208 b, respectively) to        align cap (216) held by chuck (205) with reaction vessel (101)        and to hold jaws (208 a, 208 b) in a closed position.    -   x. Reaction vessel (101) is recapped.    -   y. Sample container (210) is moved to input rack (103).    -   z. Reaction vessel (101) is optionally mixed.    -   aa. Reaction vessel (101) is moved to output rack/incubator        (104/105) or dedicated incubator (504) for incubation.    -   bb. If reaction vessel (101) is positioned in dedicated        incubator (504), after incubation the reaction vessel (101) is        moved to output rack (104).

One of skill in the art that one or more of the above processes canoccur simultaneously. The above automated protocols are provided by wayof example only such that modifications of the number of steps, whathappens in each step, and the number of processes occurring in aparticular order or simultaneously may be changed or altered withoutaffecting the subject matter of the present invention.

One of skill in the art would appreciate that the processing timerequired to process each sample has a direct effect on the number ofsamples that can be prepared in a given time period. Manipulation of theprocessing time may have a detrimental impact on processing accuracy andcan increase the risk of contamination, though a variety of sampleprocessing times are contemplated with the caveat that downtime betweensample processing is kept to a minimum.

Sample processing protocols that incorporate a reagent addition and/orincubation step (e.g., processing SUREPATH® samples) are slightly morecomplicated than non-reagent or non-incubation protocols. In the case ofprocessing SUREPATH® samples a reagent addition step and an incubationstep are required to fully prepare a sample. The rate limiting step forSUREPATH® samples in a frequent embodiment is the incubation time forsamples requiring incubation. For example, a 2 hour sample incubation at65° C. will affect the overall throughput of the instrument. Instrumentdowntime can be minimized and throughput can be maximized in batches ofsamples containing samples requiring incubation by reducing incubationtimes (e.g., down to about 1 hour), increasing the number of samplesincubated at any given time, and/or reducing the number of slots in theoutput rack.

Sample incubation time can vary over a period of time. For example, inthe case of an LBC sample the incubation time can be about 35 minutes,about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes,about 90 minutes, about 105 minutes, or about 120 minutes. Theincubation temperature occasionally varies as well. For example, theincubation temperature may be at or about 37° C., at or about 65° C., orbetween about 37° C. and 65° C. Occasionally, the incubation time may beat or about 90° C., or between about 37° C. and 90° C. In occasionalembodiments the incubation temperature is above or below 65° C. In anoccasional embodiment requiring incubation in output racks, theinstrument will generally fully populate an output rack with, e.g., 15samples before the incubation process is started. In such an embodimentthe processing time is about 1 minute 30 seconds, or about a minute, orabout less than a minute per sample prior to the incubation step.

In the frequently preferred embodiment that provides incubation ofreaction vessels in a dedicated incubator (rather than in the sampleoutput rack) having about 120 incubation slots, high throughput ratescan be maintained since incubation may begin when a reaction vessel ispositioned in the incubator, without having to wait until an output rackis fully populated. The sample processing instrument, for example, canbe configured to monitor the incubation time of each reaction vesselcontained in the dedicated incubator. Similarly, in such an embodiment alarge number of samples can be incubated at any particular time withoutcommandeering output rack space, thus permitting a continuous flow ofnon-incubated samples through to the input ranks while concurrentlyprocessing samples requiring incubation. Although the processing timefor any particular batch (e.g., a full output rack of, for example, 15samples) of incubated samples occasionally does not decrease though theuse of a dedicated incubator, throughput advantages are realized sinceoutput rack use flexibility is maximized. For example, any particularoutput rack can be populated with samples containing reaction vesselsthat have been incubated and those that have not been incubated. In suchan embodiment involving an output rack having, for example, 15 slots,these slots can be filled with up to 15 reaction vessels that have beenincubated and up to 15 reaction vessels that have not been incubated. Insuch circumstances it is unnecessary to await the completion of theincubation of 15 reaction vessels to fill an output rack; rather therack can be populated with any number of reaction vessels that havecompleted their incubation, while the remaining slots in the output rackare filled with non-incubated reaction vessels. Accordingly, in afrequently preferred embodiment the sample processing instrument iscapable of processing one sample per minute during the entirety of an 8hour work day, excluding instrument startup and shutdown time,regardless of whether the samples require incubation or not.

It will be understood by one of skill in the art that varying incubationtime, the number of slots in a sample output rack, and/or permittingpartial filling an output rack will correspondingly affect the time tocompletion of one or more samples, including a batch of samples. Forexample, if the incubation time is reduced from 2 hours, the number ofincubation slots can be decreased while maintaining a similarthroughput. Unless specifically indicated, the present invention is notlimited to a specific incubation time, amount of samples in a sampleinput rack, number of sample input rack slots, number of slots in anoutput rack, number of output rack slots, number of incubators, numberof robotic arms, number of pick-and-place mechanisms, or number ofsample processing stations.

In one embodiment the instrument is modular such that the number ofincubator slots can be altered to more or fewer than 120. In addition,the sample processing instrument may be outfitted with additional samplein out or output slots, for example 4, 5, 6, 7, 8 or more input oroutput slots, which permits increased walk-away time by the user whileincreasing system throughput.

In one embodiment the instrument is designed to process any combinationof sample racks containing samples requiring and not requiringincubation at any time, while minimizing dead time. This feature allowsthe user random access to the instrument in batches of 1-8 specimens (anexemplary number of specimen held in an input rack). The instrumentsoftware will balance time to next result and throughput based on adefined set of rules, taking into account the incubation time requiredfor the samples in the system. In a preferred embodiment, the sampleprocessing rules are the following: (1) Finish loading current outputrack, (2) process all samples requiring incubator up to incubation, and(3) process all samples not requiring incubation. Often in such anembodiment the output rack may be populated with incubated andnon-incubated samples, depending on how many samples completed theirincubations while the output rack was being populated. For example, inone embodiment when a sample completes incubation it is immediatelytransferred to the next, available slot in an output rack, whether it isan empty or partially filled output rack. One of skill in the art wouldunderstand that the time period between incubation completion andtransfer to an output rack may be limited by, for example, theavailability of the pick and place mechanism of the instrument to effectsuch a transfer.

As noted, the instrument is designed to maximize throughput regardlessof the type of sample being processed. The embodiments and examplesdiscussed herein are provided by way of illustration only. As noted, thenumber of input and output slots (including number of incubators) can bedeceased or increased in a manner that will affect overall throughput,with the limiting factors comprising incubation time and processing timewithin the sample processing station. Accordingly, in one embodiment theinstrument incorporates one or more sample processing stator(s) togetherwith, optionally, a correspondingly increased number of input slots andincubator slots and robot arms containing a pipettor and/or pick andplace mechanisms. It is contemplated that this configuration willincrease the throughput versus the examples discussed above, but at theexpense of a larger bench-top footprint.

Another limiting factor to increasing throughput is the overallfootprint of the instrument. Often laboratory space is very limited suchthat only smaller, bench-top style instruments can be accommodated. Thepresent invention fulfills this need by providing a fully automatedsample processing solution in a compact package. As such, it is anobject of the present invention to provide a compact instrument capableof automated sample processing of multiple sample types. For example, inone preferred embodiment the instrument is a bench-top instrument.

Capacity

The consumable and liquid/solid waste capacity often dictate the maximumnumber of tests the instrument can perform before specimen processing isstopped and consumables are reloaded and waste is removed. In oneembodiment the consumables and waste bins are sized for processing amaximum of 96 samples. In another embodiment, the consumables and wastebins are sized for processing a maximum of 192 samples. In a furtherembodiment, the consumables and waste bins are sized to accommodate thenumber of samples and volume of liquid and solid waste generated in afull shift of use of the instrument, such as processing up to about 5-10samples.

The waste bin is frequently used in the event that a sample processingfalls, where the failed sample is discarded in the waste bin. Inaddition, in one embodiment the waste bin is utilized as part of thesample processing process where it acts as a drip catch for caps removedfrom sample containers (102, 210, 211) and pipette tips containingsample or reagent. In one embodiment, this drip catch can be utilizedduring the period of time it takes the sample processing stationcarousel (209) to rotate to the service position (depicted in FIG. 2 )for sample aspiration or dispense. In another embodiment, a drip catchor drip tray (202) is included as a component of the sample processingstation (107). In an occasional embodiment, the drip catch or drip traycomprises a portion that is in fluid communication with the liquid wastebin and another portion capable of positioning below (a) a cap removedfrom a sample container, or (b) a pipette tip containing sample orreagent. In any event, the liquid waste bin (502) is frequentlyconfigured to have a capacity to hold all the liquid waste generated ina single shift or a single day of operation.

In one embodiment, the input racks (103) are sized to hold up to about 8LBC sample containers (102, 210, 211) in addition to 8 reaction vessels(101). In this embodiment the instrument is designed to hold up to 8input racks (103) for a total of 64 LBC samples. To run 540 samples thatdo not require additional reagents or incubation, the 8 sample inputracks (103) are loaded 9 times, for example. In the case where samplesrequiring additional reagent and incubation are processed, the inputracks (103) are loaded 6 times to process 360 LBC specimens, forexample.

In one exemplary embodiment the output drawer is sized to contain atleast 4 or up to about 8 output racks (104), each capable of holding 15reaction vessels for a total of 120 reaction vessels. The instrument canbe configured to require that the output racks (104) have their topcovers (304), if otherwise part of the output rack, removed while beingused in the instrument, which permits loading of the reaction vessels(103) into the racks. In this example, to process 540 samples. Involvesremoval of 36 output races (104), and to process 360 samples involvesremoval of 24 output racks (104) over the course of a shift.

In one embodiment, the instrument has one or more drawers or cabinetsdedicated to consumables and waste. Pipette tip trays (110) (e.g., twoor more trays of 96 pipette tips) are loaded into the consumable draweror cabinet along with one or more reagent bottle(s) (503) required forsamples requiring additional reagent. Frequently, a barcode reader (notpictured) is incorporated in optical communication with the consumabledrawer or cabinet, such that when the drawer is closed or consumablesare placed in the cabinet, one or more of the consumables are thenscanned to determine various information about the consumable, forexample, lot number, expiration date, total volume, volume remaining,type of reagent, etc. Often, however, the consumables are scanned priorto closing the cabinet or drawer. In such embodiments the particularconsumable, for example the reagent bottle, will contain a barcodeencoding the necessary or desired information.

In one embodiment, the reagent bottle (503) will generally havesufficient volume to process at least 96 samples, or at least about 120samples, or at least about 190 samples, or up to about 360 samples,requiring additional reagent (e.g., SUREPATH® samples). Additionalreagent bottles, or a larger reagent bottle, may alternatively beincorporated. For example, in one embodiment the reagent bottle (503)will generally have sufficient volume to process at least all of thesamples in a shift, or multiple shifts. The consumable drawer or cabinetis often locked so the user cannot inadvertently open it duringoperation.

Preparing and Loading the Instrument

In one exemplary embodiment, the first step in preparing the instrumentfor a run is to service the consumable drawer. In one embodiment, theinstrument will display the number of remaining samples that it canprocess before requiring replenishment of reagents, pipette tips,emptying of waste bins, shifting reaction vessels to an output rack,replacement of input racks, and/or replacement of output racks, if thenumber of remaining samples to be processed is less than the desirednumber of preparations to be performed, the consumable drawer will oftenbe accessed and loaded/emptied. The instrument is then capable oftracking what pipette tips have been used and how many tips are left,for example, by use of machine vision. See FIG. 12 , for example. Thereagent bottle (503) is, in one embodiment, monitored by a liquid levelsensor to determine the number of remaining preparations that can beperformed with the remaining reagent. In a preferred embodiment, theliquid level detection functionality of the pipettor is utilized tomonitor the amount of reagent remaining in the reagent bottle (503).With regard to solid waste, the waste bin (108) can be emptied each timethe waste bin drawer is opened

The next step in this embodiment is to apply marching barcode labels tothe sample containers (102, 210, 211) and the reaction vessels (101) andload them into the appropriate sample input rack. Once all input racks(103) have been loaded, they are inserted into the instrument. In anexemplary embodiment machine vision is utilized to detect the containeror vessel positions in each rack that are populated to provide a fullinventory of input racks (103) in the instrument.

In another step of this embodiment, the output racks (104) are loadedinto the instrument. The output racks (104) have their top cover (304)removed (if present) and also must be empty. In an exemplary embodimentmachine vision is utilized to check or verify whether the output racks(104) are empty. If a newly inserted output rack (104) is not empty thesystem will notify the user.

In another step of this embodiment machine vision is utilized to trackthe inventory of the incubator (504). Machine vision, therefore, as itis utilized in the present instrument can accurately determine, at anygiven time, the inventory of the instrument, including the incubator(504), input racks (103), output racks (104), solid waste bin (108), andtip trays (110).

Instrument Fluidic Management

In a preferred embodiment the instrument incorporates a variety ofmeasures and devices to ensure controlled fluid management. For example,in one embodiment the instrument has a single pipettor arm (112) with apipettor (406) that utilizes both capacitive and pressure based fluiddetection (LLD) and pressure based aspiration/dispense verification(RDV). In this embodiment a precision dry syringe pump is used toaccurately aspirate and dispense volumes from, for example, 25 to 1000μL. The syringe pump will often include a rotary encoder to verify themotor has not stalled or failed. Built into the pump between the syringeand the pipette tip is a pressure transducer that records the pressurewaveform when dispensing and/or aspiration occurs. Characteristics ofthe curve are used to verify dispense/aspiration process (RDV). Aconductive pipette tip is frequently attached to the syringe pumpthrough a stainless steel interface that conducts an oscillatingcurrent, used to measure changes in capacitance. When the pipette tiptouches fluid, the capacitance changes and can be detected through theliquid level detection (LLD) circuitry. See, e.g., U.S. Pat. Nos.4,977,786, 5,083,470, and 7,479,391, each of which is incorporatedherein by reference.

The fluid levels in the reagent bottles are often detected with LLD, andthe volume is calculated based on the known bottle geometry. The reagentbottle is frequently keyed in such a way that it cannot be mixed up withother bottles within the system.

In a frequent embodiment, waste fluid is removed from failed reactionvessels and placed in the liquid waste reservoir using the pipettor. Inthis circumstance, the targeted reaction vessels will be liquid leveldetected to determine the amount of liquid to be removed. Liquid wastewill be aspirated from the reaction vessel and dispensed into the liquidwaste bin. The level of the liquid waste reservoir is also measured byLLD to notify the user when servicing is required.

Electronics Design

In one embodiment, the electronic design for the instrument includes aController Area Network (CANbus) that distributes power andcommunications between the master PC controller and the system modules.The CANbus and all System peripherals are interfaced to the master PCcontroller via Ethernet and USB interfaces, for example as depicted inFIG. 13 .

In another preferred embodiment, the electronic design for theinstrument relies on power line communication (PLC), which permitscommunication signals to be transmitted over power lines in theinstrument. See, e.g., POWER LINE COMMUNICATIONS; THEORY ANDAPPLICATIONS FOR NARROWBAND AND BROADBAND COMMUNICATIONS OVER POWERLINES (H. C. Ferreira et al. eds., John Wiley & Sons Ltd. 2010). PLCoffers certain advantages over CANbus, such as permitting high datatransfer rates and utilization of a variety of protocols, such as theCANbus protocol, TCP/IP, among others. Moreover, PLC reduces complexityin the system while offering increased reliability by reducing thenumber of wires/cables extending between instrument parts. PLC isespecially advantageous in moving parts since the number of potentialwire/cable pinch-points are reduced and less area is occupied bywires/cables and, if present, their associated conduits.

In one frequent embodiment, the PC will run a stripped down OS. Any timecritical activities are handled at the module controller level, and eachmodule has its own controller responsible for running its specifictasks. Commands are, for example, sent down to the modules via theCANbus network. Each module controller contains its own specific set ofcommands and parameters. Controllers are able to post module status tothe master controller at any time.

All documents referred to herein are hereby incorporated by referenceherein. No document, however, is admitted to be prior art to the claimedsubject matter.

While the invention has been described in connection with what arepresently considered to be the most practical and preferred embodiments,it is to be understood that the invention is not to be limited to thedisclosed embodiments, but, on the contrary, is intended to include allmodifications and variations encompassed within the scope of thefollowing appended claims.

Furthermore, those of the appended claims which do not include languagein the “means for performing a specified function” format permittedunder 35 U.S.C. § 112, ¶6, are not intended to be interpreted under 35U.S.C. § 112, ¶6, as being limited to the structure, material, or actsdescribed in the present specification and their equivalents.

The invention claimed is:
 1. A processing station for automaticallyprocessing a biological sample, comprising: a rotatable platformconfigured to rotate around a central axis of rotation, two or morecontainer holders arranged in spatially distinct locations on therotatable platform, wherein each of the container holders is configuredto hold a container and to rotate about a secondary axis of rotationthat is associated with that container holder and is radially spacedfrom the central axis of rotation; a capping/decapping mechanism locatedabove the rotatable platform and configured and controlled by acontroller to cap and decap a container held in one of the containerholders positioned below the capping/decapping mechanism, wherein thecapping/decapping mechanism comprises: a chuck configured to grasp a capof a container held in one of the container holders; an elevatorconfigured to move the chuck between a lowered position and a raisedposition with respect to the container held in the container holder; anda chuck guide movable with the chuck and configured to contact thecontainer holder as the chuck is lowered by the elevator to position thechuck with respect to the container held in the container holder.
 2. Theprocessing station of claim 1, wherein the chuck guide comprises a yokewith opposed arms, and wherein the opposed arms are configured tocontact the container holder as the chuck is lowered by the elevator toposition the chuck with respect to the container held in the containerholder.
 3. The processing station of claim 2, further comprising aspindle disposed on each of the opposed arms, wherein the spindles areconfigured to contact the container holder as the chuck is lowered bythe elevator to position the chuck with respect to the container held inthe container holder.
 4. The processing station of claim 1, wherein eachcontainer holder comprises opposed jaws between which the container isheld and each jaw includes a beveled shoulder, wherein the chuck guidecomprises a yoke with opposed arms and a spindle disposed on each of theopposed arms, and wherein each spindle is configured to contact one ofthe beveled shoulders of the container holder as the chuck is lowered bythe elevator to position the chuck with respect to the container held inthe container holder.
 5. The processing station of claim 4, wherein eachcontainer holder includes a tension band extending between the opposedjaws.
 6. The processing station of claim 2, wherein the yoke has acurved shape.
 7. The processing station of claim 1, further comprising adrip tray configured and controlled by the controller to be movablebetween a first position not under the chuck and a second position underthe chuck when the chuck is moved to the raised position by theelevator.
 8. The processing station of claim 7, wherein the drip tray isrotatable between the first position and the second position about atertiary axis that is different than the central axis of the rotatableplatform.
 9. The processing station of claim 1, further comprising acontroller in communication with the rotatable platform and thecapping/decapping mechanism and configured to: (i) activate therotatable platform to rotate about the central axis of rotation untilone of the container holders is positioned beneath the chuck of thecapping/decapping mechanism; (ii) activate the elevator to move thechuck to the lowered position and activate the chuck to grasp the cap ofthe container in the one container holder; (iii) activate thecapping/decapping mechanism to remove the grasped cap from thecontainer; and (iv) after the cap is removed from the container,activate the elevator to move the chuck to the raised position.
 10. Theprocessing station of claim 1, wherein each of the two or more containerholders is configured to rotate about the secondary axis associated withthe respective container holder simultaneously with rotation of therotatable platform about the central axis to mix the contents of anycontainer held in one of the container holders.
 11. The processingstation of claim 10, wherein the rotatable platform and the two or morecontainer holders are configured to rotate in opposite directions. 12.The processing station of claim 1, further comprising an automatedpipettor movably positioned with respect to the rotatable platform andcomprising a pipette tip and configured to selectively aspirate anamount of fluid into the pipette tip or dispense an amount of fluid fromthe pipette tip and to move the pipette tip with respect to therotatable platform to enable the pipette tip to access a containercarried on the rotatable platform.
 13. The processing station of claim1, wherein the two or more container holders are positioned on theperiphery of the rotatable platform.
 14. The processing station of claim1, comprising three container holders.
 15. The processing station ofclaim 1, wherein each of the container holders is configured to holddifferent containers, the different containers comprise two or moredifferent containers, and at least one of the two or more differentcontainers has at least a width, a height, or a diameter that differsfrom one other of the two or more different containers.
 16. Theprocessing station of claim 1, further comprising a data scanningmechanism configured to scan information on an outer surface of acontainer while the container is positioned in one of the two or morecontainer holders.
 17. The processing station of claim 16, wherein thedata scanning mechanism comprises a barcode scanner.
 18. The processingstation of claim 16, further comprising a printer module in datacommunication with the data scanning mechanism such that the printermodule receives information scanned by the data scanning mechanism andis configured to apply machine-readable indicia on a surface of areaction vessel, the machine-readable indicia applied to the reactionvessel including indicia relating to information scanned on thecontainer by the data scanning mechanism.
 19. The processing station ofclaim 18, wherein the information scanned on the container and themachine readable indicia applied to the reaction vessel comprise barcodes.
 20. The processing station of claim 18, wherein the printermodule is a thermal printer configured to print indicia onto a label onthe reaction vessel comprising thermally sensitive print media.
 21. Amethod for processing a biological sample comprising: rotating a firstcontainer and a second container about a central axis of rotation whilesimultaneously rotating each of the first container and the secondcontainer about a secondary axis of rotation that is associated with thecontainer and is radially spaced from the central axis of rotation;positioning the first container beneath a capping/decapping mechanismcomprising a chuck configured to grasp a cap of the first container andan elevator configured to move the chuck between a lowered position anda raised position with respect to the first container; moving the chuckto the lowered position with the elevator, contacting a portion of thefirst container holder with a portion of the elevator to position thechuck with respect to the container held in the container holder,grasping the cap of the first container with the chuck, and removing thecap from the first container with the capping/decapping mechanism; andafter removing the cap from the first container, moving the chuck andthe cap grasped therein to the raised position with the elevator. 22.The method of claim 21, wherein contacting a portion of the firstcontainer holder with a portion of the elevator to position the chuckwith respect to the container held in the container holder comprisescontacting the first container holder with a chuck guide of theelevator, wherein the chuck guide is movable with the chuck and isconfigured to contact the container holder as the chuck is lowered bythe elevator to position the chuck with respect to the container held inthe container holder.
 23. The method of claim 22, wherein the chuckguide comprises a yoke with opposed arms, and wherein the opposed armsare configured to contact the container holder as the chuck is loweredby the elevator to position the chuck with respect to the container heldin the container holder.
 24. The method of claim 23, wherein the chuckguide further comprises a spindle disposed on each of the opposed arms,wherein the spindles are configured to contact the container holder asthe chuck is lowered by the elevator to position the chuck with respectto the container held in the container holder.
 25. The method of claim24, wherein each container holder comprises opposed jaws between whichthe container is held and each jaw includes a beveled shoulder, andwherein each spindle is configured to contact one of the beveledshoulders of the container holder as the chuck is lowered by theelevator to position the chuck with respect to the container held in thecontainer holder.
 26. The method of claim 25, wherein each containerholder includes a tension band extending between the opposed jaws. 27.The method of claim 21, further comprising moving a drip tray from afirst position not under the chuck to a second position under the chuckmoved to the raised position by the elevator.